MPS-1 is a K+ channel β-subunit and a serine/threonine kinase


We report the first example of a K+ channel β-subunit that is also a serine/threonine kinase. MPS-1 is a single–transmembrane domain protein that coassembles with voltage-gated K+ channel KVS-1 in the nervous system of the nematode Caenorhabditis elegans. Biochemical analysis shows that MPS-1 can phosphorylate KVS-1 and other substrates. Electrophysiological analysis in Chinese hamster ovary (CHO) cells demonstrates that MPS-1 activity leads to a significant decrease in the macroscopic current. Single-channel analysis and biotinylation assays indicate that MPS-1 reduces the macroscopic current by lowering the open probability of the channel. These data are consistent with a model that predicts that the MPS-1–dependent phosphorylation of KVS-1 sustains cell excitability by controlling K+ flux.

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Figure 1: MPS-1 shows characteristic protein kinase motifs.
Figure 2: MPS-1 phosphorylates MBP in vitro.
Figure 3: MPS-1 activity can be detected by antibodies to phosphoserine and phosphothreonine (anti-pS/pT).
Figure 4: MPS-1 phosphorylates KVS-1 in CHO cells.
Figure 5: MPS-1 kinase activity decreases the macroscopic current.
Figure 6: MPS-1 decreases the open probability of the KVS-1 channel.
Figure 7: Fluctuation analysis of KVS-1 and KVS-1–MPS-1 channels.


  1. 1

    MacKinnon, R. Determination of the subunit stoichiometry of a voltage-activated potassium channel. Nature 350, 232–235 (1991).

    CAS  Article  Google Scholar 

  2. 2

    Doyle, D. et al. The structure of the potassium channel: molecular bases for K+ conduction and selectivity. Science 280, 69–77 (1998).

    CAS  Article  Google Scholar 

  3. 3

    Abbott, G. & Goldstein, S. A superfamily of small potassium channel subunits: form and function of the MinK-related peptides (MiRPs). Q. Rev. Biophys. 31, 357–398 (1998).

    CAS  Article  Google Scholar 

  4. 4

    McCrossan, Z.A. & Abbott, G.W. The MinK-related peptides. Neuropharmacology 47, 787–821 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Wang, Y., Park, K.H., Hernandez, L., Cai, S.-Q. & Sesti, F. Biophysical and biomedical aspects of KCNE potassium channel ancillary subunits. in Recent Research Developments in Biophysics Vol. 3 Part II (ed. Pandalai, S.G.) 351–363 (Transworld Research Network, Trivandrum, India, 2004).

    Google Scholar 

  6. 6

    Park, K.H., Hernandez, L., Cai, S.Q., Wang, Y. & Sesti, F. A Family of K+ Channel Ancillary Subunits Regulate Taste Sensitivity in Caenorhabditis elegans. J. Biol. Chem. 280, 21893–21899 (2005).

    CAS  Article  Google Scholar 

  7. 7

    Anantharam, A. et al. RNA interference reveals that endogenous Xenopus MinK-related peptides govern mammalian K+ channel function in oocyte expression studies. J. Biol. Chem. 278, 11739–11745 (2003).

    CAS  Article  Google Scholar 

  8. 8

    Takumi, T., Ohkubo, H. & Nakanishi, S. Cloning of a membrane protein that induces a slow voltage-gated potassium current. Science 242, 1042–1045 (1988).

    CAS  Article  Google Scholar 

  9. 9

    Tai, K. & Goldstein, S. The conduction pore of a cardiac potassium channel. Nature 391, 605–608 (1998).

    CAS  Article  Google Scholar 

  10. 10

    Melman, Y.F., Um, S.Y., Krumerman, A., Kagan, A. & McDonald, T.V. KCNE1 binds to the KCNQ1 pore to regulate potassium channel activity. Neuron 42, 927–937 (2004).

    CAS  Article  Google Scholar 

  11. 11

    Chen, H., Sesti, F. & Goldstein, S.A. Pore- and state-dependent cadmium block of I(Ks) channels formed with MinK-55C and wild-type KCNQ1 subunits. Biophys. J. 84, 3679–3689 (2003).

    CAS  Article  Google Scholar 

  12. 12

    Sesti, F. & Goldstein, S.A. Single-channel characteristics of wild-type IKs channels and channels formed with two minK mutants that cause long QT syndrome. J. Gen. Physiol. 112, 651–663 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Sesti, F., Tai, K.K. & Goldstein, S.A. MinK endows the I(Ks) potassium channel pore with sensitivity to internal tetraethylammonium. Biophys. J. 79, 1369–1378 (2000).

    CAS  Article  Google Scholar 

  14. 14

    Yang, Y. & Sigworth, F.J. Single-channel properties of IKs potassium channels. J. Gen. Physiol. 112, 665–678 (1998).

    CAS  Article  Google Scholar 

  15. 15

    Pusch, M. Increase of the single-channel conductance of KvLQT1 potassium channels induced by the association with minK. Pflugers Arch. 437, 172–174 (1998).

    CAS  Article  Google Scholar 

  16. 16

    Marx, S.O. et al. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science 295, 496–499 (2002).

    CAS  Article  Google Scholar 

  17. 17

    Kurokawa, J., Chen, L. & Kass, R.S. Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel. Proc. Natl. Acad. Sci. USA 100, 2122–2127 (2003).

    CAS  Article  Google Scholar 

  18. 18

    McCrossan, Z.A. et al. MinK-related peptide 2 modulates Kv2.1 and Kv3.1 potassium channels in mammalian brain. J Neurosci. 3;23, 8077–91 (2003).

    Article  Google Scholar 

  19. 19

    Splawski, I., Tristani-Firouzi, M., Lehmann, M.H., Sanguinetti, M.C. & Keating, M.T. Mutations in the hMinK gene cause long QT syndrome and suppress IKs function. Nat. Genet. 17, 338–340 (1997).

    CAS  Article  Google Scholar 

  20. 20

    Piccini, M. et al. KCNE1-like gene is deleted in AMME contiguous gene syndrome: identification and characterization of the mouse homologues. Genomics 60, 251–257 (1999).

    CAS  Article  Google Scholar 

  21. 21

    Abbott, G. et al. MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 104, 217–231 (2001).

    CAS  Article  Google Scholar 

  22. 22

    Abbott, G. et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97, 175–187 (1999).

    CAS  Article  Google Scholar 

  23. 23

    Sesti, F. et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc. Natl. Acad. Sci. USA 97, 10613–10618 (2000).

    CAS  Article  Google Scholar 

  24. 24

    Splawski, I. et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 102, 1178–1185 (2000).

    CAS  Article  Google Scholar 

  25. 25

    Manning, G., Whyte, D.B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).

    CAS  Article  Google Scholar 

  26. 26

    Bianchi, L., Kwok, S.M., Driscoll, M. & Sesti, F. A potassium channel-MiRP complex controls neurosensory function in Caenorhabditis elegans. J. Biol. Chem. 278, 12415–12424 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Hwang, I-S., Kim, J-H. & Choi, M-U. Kinetic study of dephosphoryltation of Myelin Basic Protein by some protein phosphates. Bull. Korean Chem. Soc. 18, 428–432 (1997).

    CAS  Google Scholar 

  28. 28

    Miyamoto, E. & Kakiuchi, S. In vitro and in vivo phosphorylation of myelin basic protein by exogenous and endogenous adenosine 3′:5′-monophosphate-dependent protein kinases in brain. J. Biol. Chem. 249, 2769–2777 (1974).

    CAS  Google Scholar 

  29. 29

    Laurino, J., Colca, J., Pearson, J., DeWald, D. & McDonald, J. The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Arch. Biochem. Biophys. 265, 8–21 (1988).

    CAS  Article  Google Scholar 

  30. 30

    Tonks, N., Diltz, C. & Fischer, E. CD45, an integral membrane protein tyrosine phosphatase. Characterization of enzyme activity. J. Biol. Chem. 265, 10674–10680 (1990).

    CAS  Google Scholar 

  31. 31

    Ryazanova, L.V., Dorovkov, M.V., Ansari, A. & Ryazanov, A.G. Characterization of the protein kinase activity of TRPM7/ChaK1, a protein kinase fused to the transient receptor potential ion channel. J. Biol. Chem. 279, 3708–3716 (2004).

    CAS  Article  Google Scholar 

  32. 32

    Beeton, C.A., Chance, E.M., Foukas, L.C. & Shepherd, P.R. Comparison of the kinetic properties of the lipid- and protein-kinase activities of the p110alpha and p110beta catalytic subunits of class-Ia phosphoinositide 3-kinases. Biochem. J. 350, 353–359 (2000).

    CAS  Article  Google Scholar 

  33. 33

    Rintamaki, E. et al. Phosphorylation of light-harvesting complex II and photosystem II core proteins shows different irradiance-dependent regulation in vivo. Application of phosphothreonine antibodies to analysis of thylakoid phosphoproteins. J. Biol. Chem. 272, 30476–30482 (1997).

    CAS  Article  Google Scholar 

  34. 34

    Zheng, B. et al. The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400, 169–173 (1999).

    CAS  Article  Google Scholar 

  35. 35

    Du, P. et al. Phosphorylation of serine residues in histidine-tag sequences attached to recombinant protein kinases: a cause of heterogeneity in mass and complications in function. Protein Expr. Purif. published online 7 June 2005 (10.1016/j.pep.2005.04.018).

  36. 36

    Sigworth, F.J. The variance of sodium current fluctuations at the node of Ranvier. J. Physiol. (Lond.) 307, 97–129 (1980).

    CAS  Article  Google Scholar 

  37. 37

    Ryazanov, A.G., Pavur, K.S. & Dorovkov, M.V. Alpha-kinases: a new class of protein kinases with a novel catalytic domain. Curr. Biol. 9, R43–R45 (1999).

    CAS  Article  Google Scholar 

  38. 38

    Runnels, L.W., Yue, L. & Clapham, D.E. TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 291, 1043–1047 (2001).

    CAS  Article  Google Scholar 

  39. 39

    Drennan, D. & Ryazanov, A.G. Alpha-kinases: analysis of the family and comparison with conventional protein kinases. Prog. Biophys. Mol. Biol. 85, 1–32 (2004).

    CAS  Article  Google Scholar 

  40. 40

    Barhanin, J. et al. K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 384, 78–80 (1996).

    CAS  Article  Google Scholar 

  41. 41

    Schroeder, B. et al. A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature 403, 196–199 (2000).

    CAS  Article  Google Scholar 

  42. 42

    Melman, Y.F., Domenech, A., de la Luna, S. & McDonald, T.V. Structural determinants of KvLQT1 control by the KCNE family of proteins. J. Biol. Chem. 276, 6439–6444 (2001).

    CAS  Article  Google Scholar 

  43. 43

    Ward, S. Chemotaxis by the nematode Caenorhabditis elegans: identification of attractants and analysis of the response by use of mutants. Proc. Natl. Acad. Sci. USA 70, 817–821 (1973).

    CAS  Article  Google Scholar 

  44. 44

    Bargmann, C. & Mori, I. in C. elegans II (eds. Riddle, D.L., Blumenthal, T., Meyer, B.T. & Priess, J.R.) Ch. 25 717–37 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1997).

    Google Scholar 

  45. 45

    Bargmann, C.I. & Horvitz, H.R. Chemosensory neurons with overlapping functions direct chemotaxis to multiple chemicals in C. elegans. Neuron 7, 729–742 (1991).

    CAS  Article  Google Scholar 

  46. 46

    Sakmann, B. & Neher, E. (eds) Single-Channel Recording (Plenum Press, New York and London, 1995).

    Google Scholar 

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We thank L. Runnels, A. Ryazanov and J. Lenard for their comments on the manuscript and Fulvio Sesti for help with the graphics. This work was supported by grant R01GM68581-01 from the US National Institutes of Health to F.S.

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Correspondence to Federico Sesti.

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Cai, S., Hernandez, L., Wang, Y. et al. MPS-1 is a K+ channel β-subunit and a serine/threonine kinase. Nat Neurosci 8, 1503–1509 (2005).

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